Considerations for new dual-acting bronchodilator treatments for chronic obstructive pulmonary disease

Abstract

Current guidelines recommend treatment with one or more bronchodilators for chronic obstructive pulmonary disease (COPD) patients. Combination therapy with long-acting muscarinic antagonists (LAMA) and long-acting β₂-agonists (LABA) should be recommended in patients who are not fully controlled with one of them. In this article, two closely related approaches to provide long-acting treatments are compared: the LABA/LAMA fixed-dose combination therapy, and the dual-acting muscarinic receptor antagonist and β₂-adrenoceptor agonist (MABA). The author in that study concludes that both approaches have been shown to provide clinically enhanced bronchodilator activity that is superior to that offered by current standard treatment. LAMA/LABA fixed-dose combinations are expected to become a new standard in the treatment of COPD. It is important to know the characteristics of the different LAMA or LABA, the inhalation device and the duration of action, because diversity can help to personalize the treatment. Dose-finding studies are required. It is also required to investigate the existence of pharmacodynamics or pharmacokinetic interactions between the components as well as the safety profile. MABA represent an alternative to these combinations, but there is little clinical data yet reported. They have the potential to act as a useful platform for the development of triple therapy in one inhaler.

Keywords::

• chronic obstructive pulmonary disease
• fixed-dose combinations
• long acting β₂-agonists
• long-acting muscarinic antagonists

1. Introduction

According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy, bronchodilators are the cornerstone of symptomatic treatment for chronic obstructive pulmonary disease (COPD). Current guidelines for the effective management of this disease recommend treatment with one or more long-acting bronchodilators for patients with moderate-to-severe COPD. Two classes of long-acting inhaled bronchodilators are available: long acting β₂-agonists (LABA) and long-acting muscarinic antagonists (LAMA). LABA directly induce bronchodilation by relaxing airway smooth muscle through stimulation of β₂-adrenergic receptors, whereas LAMA prevent acetylcholine-induced bronchoconstriction by acting as competitive antagonists on muscarinic receptors. Monotherapy should be the first choice for maintenance treatment in patients with stable COPD, whereas LAMA/LABA combination therapy should be recommended for patients with COPD who are not fully controlled with one long-acting bronchodilator to maximize bronchodilation. This is justified by their complementary mechanism of action. LABA increase the bronchodilator effect produced by LAMA by decreasing the release of acetylcholine via modulation of cholinergic neurotransmission [1]. On the other hand, LAMA antagonize the effects of acetylcholine, amplifying the bronchodilation caused by LABA [1]. Thereby, concurrent administration of a LABA with a LAMA produces superior bronchodilation compared with their individual effects, with additional benefits over dyspnea and dynamic hyperinflation, improving symptoms and exercise endurance, without increasing adverse effects. All this explains why the guidelines recommend the addition of a second bronchodilator in patients with moderate-to-severe COPD (groups B – D) to optimize symptom benefit. In particular, the GOLD 2013 strategy suggests using LAMA/LABA combination as an alternative treatment for patients in groups B (high symptoms/low risk), C (low symptoms/high risk) and D (high symptoms/high risk). However, it has been shown that a high proportion of patients at low risk for exacerbations (groups A or B) may be receiving inhaled corticosteroids (ICS) inappropriately. Some patients currently receiving combined LABA/ICS may do better on a LABA/LAMA combination. This would provide dual bronchodilation without the need for ICS treatment, and therefore without the inherent risks of ICS, as recommended by the GOLD 2013 strategy [2].

The concept of dual bronchodilation can currently be achieved with a free combination of LABA and LAMA. Nevertheless, this combination requires the administration of both drugs separately in different devices, and this would potentially affect patients' convenience and compliance. Consequently, there is a strong interest within the pharmaceutical industry in the development of new dual-acting bronchodilator treatments for COPD, muscarinic receptor antagonist and β₂-adrenoceptor agonist (MABA) combined into a single molecule [3,4].

In the January issue of Expert Opinion on Investigational Drugs, two closely related approaches to provide long-acting treatments are compared: the LABA/LAMA fixed-dose combination therapy and the dual acting MABA molecules [5]. The author in that study concludes that both approaches have been shown to provide clinically enhanced bronchodilator activity, superior to that offered by current standard treatment. On the other hand, he states that clinical results have not clearly demonstrated yet that these new combinations also provided an enhanced reduction in the frequency of disease exacerbations. However, it has recently been shown that glycopyrronium/indacaterol fixed-dose combination is superior in preventing moderate-to-severe COPD exacerbations compared with the single long-acting antimuscarinic bronchodilator glycopyrronium, with concomitant improvements in lung function and health status [6].

Fixed-dose combinations of LAMA and LABA have been shown to have an established profile of efficacy and safety in patients with moderate-to-severe COPD. They offer the potential of improving the convenience and the compliance over the use of separate inhalers, and during their development, the dose of each agent to be used in combination can be optimized [7]. Patients with COPD have several comorbidities and are likely to be on other medications. In comparison to the free-dose combinations, fixed-dose combinations provide the advantage of delivering both drugs in a single inhaler device, and thus aim at simplifying the treatment regimen, improving patient adherence. Additionally, incorporation of once-daily dosing is an important strategy to improve adherence, since it is a regimen preferred by most patients. Glycopyrronium/indacaterol [8], umeclidinium/vilanterol [9] and tiotropium/olodaterol [10] fully meet such requirements. These fixed-dose combinations are in advanced development for the treatment of COPD and have demonstrated significant broncholytic effects. Moreover, some new combinations, such as glycopyrrolate/formoterol [11] and aclidinium/formoterol [12], are under development, but these combinations have 12-h duration of action, with an expected twice-daily dosing regimen.

As previously mentioned, the principal aims in managing COPD are to achieve optimal control of symptoms and to improve patients' quality of life. In cases of severe COPD, the addition on an ICS is recommended. It has demonstrated an additional benefit for COPD patients receiving triple therapy (LAMA + LABA/ICS), including improved lung function, reduction of exacerbations and an improved quality of life in comparison to monotherapy. Therefore, the ideal combination in these patients could be a triple LAMA/LABA/ICS co-formulation. However, the co-formulation of two bronchodilators with an ICS in a single device represents an immense technical challenge. One strategy to overcome these difficulties is to design a single molecule with dual pharmacology, MABA, that could be more readily co-formulated with an ICS and would simplify triple therapy into a single inhaler [13].

The attractiveness of the MABA concept has led to the research of several candidates but only some of them have progressed to advanced clinical development. Although this approach offer benefits in terms of ease-of-use, it presents a potential limitation, as the ratio of muscarinic antagonism and β₂-agonism activities cannot be adjusted as needed and this limits dosing flexibility. Moreover, patients cannot take one agent without taking the other. However, it seems logical to expect that convenience and consequently compliance, which means adherence to the prescribed treatment, would probably be improved. A key advantage of bifunctional molecules, as mentioned previously, is that it will enable the development of triple therapy in one inhaler. By using this kind of molecule, it will reduce the number of components from three to two, thus simplifying the technical challenges associated with the development of inhaled co-formulations.

The developments described undoubtedly represent a real advance in the therapeutic strategy for COPD. As described extensively in the review by Norman, there is substantial evidence and guidance to support the use of a combination of LAMA and LABA in COPD. In fact, several fixed-dose inhalers are currently being developed following this strategy. With respect to MABA, there are still few clinical data, so it remains to be established if their use would offer any clinical benefits relative to LAMA/LABA combinations. If you consider that they are clinically effective, and well tolerated, their significance is more likely to stem from their use in addition to an ICS (triple therapy).

2. Expert opinion

Dual bronchodilation with a fixed-dose combination of LAMA and LABA is expected to become a new standard in the treatment of COPD by adding the benefits of the two components. In fact, this approach has been shown to have an established profile of efficacy and safety in patients with moderate-to-severe COPD. Several of the LAMA/LABA fixed-dose combinations in development will be delivered once daily (glycopyrronium/indacaterol, umeclidinium/vilanterol and tiotropium/olodaterol) while others (glycopyrronium/formoterol and aclidinium/formoterol) will have twice-daily dosing. This diversity of duration of action has the potential to increase the personalization of treatment to individual needs of COPD patients. Thus, for instance, once-daily combinations may be prescribed to improve adherence and, therefore, patient outcomes. By contrast, twice-daily combinations could be considered in patients who suffer from nocturnal symptoms. In any case, dose-finding studies are required to establish minimal effective doses for each agent in the combination, as it cannot be assumed that these doses would be the same as in monotherapy. It is also required to investigate the existence of possible pharmacodynamics or pharmacokinetic interactions that may occur between the components as well as the safety profile of the combinations.

Nevertheless, there are some points to keep in mind when choosing a LAMA/LABA fixed-dose combination. It is important to know if there are differences between different anticholinergic agents, tiotropium, umeclidinium, aclidinium and glycopyrronium. For instance, it has been demonstrated that the latter LAMA achieves maximal bronchodilation on the first day of dosing or have a faster onset of action than tiotropium bromide, which may offer advantages in terms of improving symptom control. We should remember that patient wake up at the nadir of their daily lung function cycle, when symptoms are most prominent, so the rapid onset of action may be critical [14]. A comparison between different LAMA is, therefore, imperative. Also, it is important to know if there are differences in LABA that could elicit a greater response when used with a specific anticholinergic agent. It could also occur that differences in the characteristics of each LAMA could influence the broncholytic response when combined with a specific LABA. Appropriate prospective studies could clarify the probable differences between them and will allow translating this information to clinical practice.

Another aspect to consider when comparing different fixed-dose combinations is the inhalation device. The new inhaler currently in development for delivery of LAMA/LABA combinations for COPD fall into three classes: pressurized metered dose inhalers (glycopyrrolate/formoterol), dry powder inhalers (glycopyrronium/indacaterol, umeclidinium/vilanterol, aclidinium/formoterol) and a propellant-free Soft Mist™ inhaler (tiotropium/olodaterol), with different profiles. Since poor inhaler technique is often a main cause of suboptimal COPD management, determining a suitable delivery device that each individual patient will be able to use can help in ensuring adequate disease management [3].

Although bifunctional molecules MABA represent an alternative to use combinations of LAMA and LABA, little clinical data have been reported yet. However, MABA have the potential to be a useful platform for the development of triple therapy (LAMA/LABA/ICS) in one inhaler. The limitations would include the fact that any contraindications to one of the drug classes will also be a contraindication for the fixed product. In addition, any reported drug-related effects would not be attributable to the responsible mechanism [15]. The main advantage is that the end product can have greater benefits than single pharmacology therapies, so it will certainly provide new treatments for the management of COPD.

At any rate, research continues to better identify targets that can change the natural history of COPD. Multicenter trials looking at genomics and biomarkers for COPD could help in personalizing treatments, leading to improved disease management and prevention for our patients.

Declaration of interest

The authors have no conflict of interest and have received no payment in the preparation of their manuscript.